This is a competitive renewal application for a NIH RO1 grant entitled Structures and Interactions of Chemokine Receptors that has been continuously funded and very successful for more than 13 years. The long-standing interest and goals in this project are to understand the structure-function relationship and mechanism of chemokines and their receptors in various pathologies and to translate such information into the development of new intervention strategies. During the past funding period, we have made significant progress towards these goals. Specifically, as described in the Progress Report, using the strategy of Synthetically and Modularly Modified Chemokines (SMM-chemokines) developed by us previously, we have designed and synthesized a novel agonist molecule of CXCR4 receptor and completed a series of studies to characterize the in vitro and in vivo biological activities of this de novo CXCR4 agonist in activating and directing neural stem cell migration. As CXCR4 plays a critical role in the migration of neural stem cells during tissue repairs, our novel CXCR4 agonist molecule has opened new possibilities for studying the mechanism of targeted human neural stem cell migration mediated by chemokine ligands and receptors and developing new therapeutics for tissue repairs. In this renewal application, we propose to apply this exciting discovery to the development of new analogs of this novel CXCR4 agonist with optimized pharmacological and biological properties as tools to further probe the structure-function relationship and mechanism of CXCR4-ligand binding and signaling and drug leads to develop new medicines for promoting stem cell-based tissue repairs. The underlying hypothesis is that de novo synthetic ligands of CXCR4, created by chemically conjugating the two molecular moieties mimicking the essential binding and signaling functions of natural chemokine ligands of CXCR4, can be novel synthetic chimera serving as new molecular probes and drug candidates.